Obesity is a prevalent health problem as an important risk factor for chronic diseases such as diabetes, hypertension, and heart disease. There are essentially no effective pharmaceutical treatments for obesity, and its incidence is on the rise. Obesity, as defined by a body mass index above 25, increased from an incidence of 24% in 1980 to 33% in 1990 in a large representative sample in the United States. One reason why it is difficult for obese individuals to lose weight is the multifactorial neuroendocrine processes that function to maintain energy homeostasis. Decreased caloric intake results in a decrease in basal metabolic rate, and even decreased energy requirements for work, that act to offset the decreased energy intake. Thus, pharmaceuticals that simply decrease food intake for alter metabolic rate are ineffective weight loss agents. A much deeper under of the neuroendocrine control of energy homeostasis is required, and this is the overall goal of this program. This application will focus on two groups of neurons strongly implicated in energy homeostasis, the arcuate nucleus neurons containing the orexigenic neuropeptide Y (NPY) and agouti gene related peptide (AGRP), and the inhibitory arcuate neurons expressing pro-opiomelanocortin (POMC). The first goal of this application will be to determine the role of the POMC and AGRP/NPY neurons in energy homeostasis. Dr. Cone (project 1) will determine the normal physiological inputs to energy homeostasis that operate via release of melanocortin or AGRP peptides in the mouse, and the mechanisms by which melanocortin and AGRP peptides regulate feeding and energy./expenditure. Dr. Cone (project 1) will determine the normal physiological inputs to energy homeostasis that operate via release of melanocortin or AGRP peptides in the mouse, and the mechanisms by which melanocortin and AGRP peptides regulate feeding and energy/ expenditure. Dr. Low (project IV) will examine the role of the opioid POMC peptide, beta-endorphin, collaboration with Dr. Cone, and the function of the POMC neurons exclusive of POMC peptide release. Dr. Simerly (project V), using normal mice and transgenic and knockout strains provided by Drs. Low and Cone, will examine the development of the POMC arcuate projections to better define the neural substrate for energy homeostasis in the rodent. Dr. Cameron (project III) will characterize the unique differences in the POMC and NPY/AGRP systems and the physiological role(s) of NPY and melanocortins in the non-human primate. Finally, Dr. Boston in collaboration with Drs. Low and Cone, will look for mutations in the POMC gene that gained in the first goal into new knowledge of and potential treatments for obesity in humans. Basic studies from the work of Drs. Cone, Low, and Simerly (projects I, IV, V) will serve to better define the fundamental neuroendocrine pathways involved in energy homeostasis, thus pointing to candidate genes to examine for linkage to human obesity and identifying potential targets for drug development. Work from Dr. Cameron's group (project III) will serve to validate these concepts in a non-human primate and also characterize aspects of these pathways that are unique to the primate. Finally, the specific hypothesis that altered levels of POMC gene expression may be a risk factor for obesity will be directly tested by Dr. Boston and his collaborators (project II).